Luisa Caniatti

Altered miRNA expression in T regulatory cells in course of multiple sclerosis.

OBJECTIVES Multiple sclerosis (MS) is a chronic inflammatory response against constituents of the central nervous system. It is known that regulatory T cells (Tregs) play a key role in the autoimmune balance and their improper function may facilitate the expansion of autoaggressive T cell clones. Recently, microRNAs (miRNAs) have been involved in autoimmune disorders and their loss-of-function in immune cells was shown to facilitate systemic autoimmune disorders. Here, we analyzed the miRNA expression profile in Tregs from MS-RR. METHODS We assessed miRNA genome-wide expression profile by microarray analysis on CD4(+)CD25(+high) T cells from 12 MS relapsing-remitting patients in stable condition and 14 healthy controls. Since CD4(+)CD25(+high) T cells comprise both T regulatory cells (CD4(+)CD25(+high)CD127(dim/-)) and T effector cells (CD4(+)CD25(+high)CD127(+)), we performed a quantitative RT-PCR on CD4(+)CD25(+high)CD127(dim/-) and CD4(+)CD25(+high)CD127(+) cells isolated from the same blood sample. RESULTS We found 23 human miRNAs differentially expressed between CD4(+)CD25(high)bona fide Treg cells from MS patients vs. healthy donors, but, conversely, among the deregulated miRNAs, members of the miR-106b-25 were found down-regulated in MS patients when compared to healthy donors in CD4(+)CD25(high)CD127(dim/-) T regulatory cells. More interesting, the ratio between Treg/Teff showed an enrichment of these microRNA in T regulatory cells derived from patients if compared to healthy controls. CONCLUSION miR-106b and miR-25 were previously shown to modulate the TGF-β signaling pathway through their action on CDKN1A/p21 and BCL2L11/Bim. TGF-β is involved in T regulatory cells differentiation and maturation. Therefore, the deregulation of this miRNA cluster may alter Treg cells activity in course of MS, by altering TGF-β biological functions.

Cognitive impairment and its relation with disease measures in mildly disabled patients with relapsing–remitting multiple sclerosis: baseline results from the Cognitive Impairment in Multiple Sclerosis (COGIMUS) study

Background Cognitive impairment is a common symptom of multiple sclerosis (MS), but the association between cognitive impairment and magnetic resonance imaging (MRI) disease measures in patients with relapsing–remitting (RR) MS is unclear. Objectives To study the prevalence of cognitive impairment and its relation with MRI disease measures in mildly disabled patients with RRMS. Methods Patients aged 18–50 years with RRMS (McDonald criteria) and an Expanded Disability Status Scale (EDSS) score ≤4.0, who were enrolled in the Cognitive Impairment in Multiple Sclerosis (COGIMUS) study, underwent baseline standardized MRI complete neurological examination and neuropsychological testing. Results A total of 550 patients were enrolled, 327 of whom underwent MRI assessments. Cognitive impairment (impaired performance in ≥3 cognitive tests) was present in approximately 20% of all patients and in the subgroup who underwent MRI. T2 hyperintense and T1 hypointense lesion volumes were significantly higher in patients with cognitive impairment (defined as impaired performance on at least three tests of the Rao’s battery) than those without. EDSS score was also significantly higher in cognitively impaired than in cognitively preserved patients. Disease duration, depression, and years in formal education did not differ significantly between cognitively impaired and cognitively preserved patients. T2 lesion volume, performance intelligence quotient, and age were significant predictors of cognitive impairment in this population. Weak correlations were found between performance on individual cognitive tests and specific MRI measures, with T1 and T2 lesion volumes correlating with performance on most cognitive tests. Conclusions Cognitive impairment occurs in approximately one-fifth of mildly disabled patients with MS and is associated with specific MRI disease measures. Assessment of cognitive function at diagnosis could facilitate the identification of patients who may benefit from therapeutic intervention with disease-modifying therapies to prevent further lesion development.

Environmental Risk Factors and Multiple Sclerosis: A Community-Based, Case-Control Study in the Province of Ferrara, Italy

The frequency of multiple sclerosis (MS) in Italy and in other areas of the world seems to have increased over time, suggesting that some environmental factors operate in its etiology. We performed a retrospective, community-based case-control study on MS in order to verify the etiologic role of selected environmental factors. We found an association between MS and higher educational level, employment in public administration, past history of allergies, and infection at an early age with measles, rubella and whooping cough. Our data seem to confirm that exogenous factors play a role in the etiology of MS although some confounding variables could have accounted for the associations.

Central nervous system involvement in Sjögren’s syndrome: unusual, but not unremarkable—clinical, serological characteristics and outcomes in a large cohort of Italian patients

OBJECTIVES To perform an observational retrospective cross-sectional case-control study to evaluate prevalence, clinical patterns and outcomes of CNS involvement in a large cohort of primary SS (pSS) patients. METHODS A total of 424 pSS patients, diagnosed according to the 2002 criteria proposed by the American-European Consensus Group, were checked for CNS involvement after exclusion of secondary causes. Demographic, clinical, seroimmunological data were compared between patients with and without CNS involvement. Neuroimaging data were also analysed. RESULTS CNS involvement was detected in 25 (5.8%) patients (24 females and 1 male) both at disease onset (52%) and later (48%) with a mean latency after diagnosis of 7 years. Diffuse (40%), focal/multifocal (36%), multiple sclerosis (MS)-like disease (20%) and isolated optic neuritis (4%) were the most common CNS clinical pictures. Disease duration, lung involvement and decreased C(4) were associated with CNS involvement, while articular manifestations were more frequently observed in patients without neurological complications. Most cases had an acute, often recurrent course with spontaneous remission or only mild neurological impairment. CONCLUSIONS CNS involvement represents a rare but not negligible complication of pSS, which may occur with a bimodal temporal pattern, both at onset and later, prompting attention in the differential diagnosis of apparently isolated neurological syndromes. Lung involvement emerged as the strongest risk factor for CNS involvement with a relative risk of 7.9, along with disease duration and decreased C(4).

Effects of immunomodulatory treatment with subcutaneous interferon beta-1a on cognitive decline in mildly disabled patients with relapsing-remitting multiple sclerosis

The objective of this study was to assess the effects of subcutaneous (sc) interferon beta-1a (IFNβ-1a) on cognition in mildly disabled patients with relapsing—remitting multiple sclerosis (RRMS). Patients aged 18—50 years with RRMS (McDonald criteria; Expanded Disability Status Scale score ≤4.0) were assigned IFNβ therapy at the physician’s discretion and underwent standardized magnetic resonance imaging, neurological examination and neuropsychological testing at the baseline and regular intervals for up to three years. This analysis included 459 patients who received sc IFNβ-1a (44 mcg: n = 236; 22 mcg: n = 223; three-year follow up was available for 318 patients). The hazard ratio for cognitive impairment over three years (44 mcg versus 22 mcg) was 0.68 (95% confidence interval [CI]: 0.480—0.972), suggesting a 32% lower risk with the higher dose treatment. At year 3, the proportion of patients who were cognitively impaired increased slightly from 23.5% at the baseline to 24.8% in the IFNβ-1a 22 mcg treatment group, but remained stable at 15.2% in the IFNβ-1a 44 mcg treatment group. The proportion of patients with cognitive impairment at year 3 was significantly higher in the 22 mcg group than in the 44 mcg group (P = 0.03), although a trend was also seen at the baseline (P = 0.058). Multivariate logistic regression (corrected for baseline cognitive deficits) indicated that treatment with the higher dose of IFNβ-1a was predictive of lower cognitive impairment at three years (odds ratio: 0.51, 95% CI: 0.26—0.99) compared with the lower dose of IFNβ-1a. These findings suggest that sc IFNβ-1a may have dose-dependent cognitive benefits in mildly disabled patients with RRMS, and may support early initiation of high-dose IFNβ-1a treatment.

Factors and comorbidities associated with first neuropsychiatric event in systemic lupus erythematosus: does a risk profile exist? A large multicentre retrospective cross-sectional study on 959 Italian patients

OBJECTIVE To analyse risk factors and comorbidities potentially associated with CNS involvement in a large cohort of Italian patients affected by SLE. METHODS A number of generic (not strictly SLE related) and specific (disease related) risk factors to which all patients have been exposed in the span of 5 years before the first neuropsychiatric (NP) event or before the last available observation were checked for and their distribution was analysed in 959 SLE patients with and without NP involvement; all the first NP events that occurred in a time frame of 10 years were recorded and categorized as SLE related or SLE unrelated. RESULTS Three hundred and twenty-six SLE patients with and 633 SLE patients without NP manifestations were included in the study. A total of 469 NP events were recorded. Headache (26.1%), cerebrovascular events (22.7%), mood disorders (8.9%), seizures (14.4%) and cognitive dysfunctions (9.5%) were the most frequent SLE-related NP events. More risk factors [mean 4.52 (2.44) vs 3.73 (2.01); P < 0.0001] were observed in patients with than without NP involvement. Overall, aPLs, LA and APS were factors more strongly associated with NP involvement. CONCLUSIONS In SLE, NP involvement and aPLs were confirmed as closely related. Furthermore, other modifiable generic risk factors, such as hypertension, carotid vasculopathy and dyslipidaemia, appeared to be related to the occurrence of cerebral vascular accident (CVA) and cognitive dysfunctions, suggesting the need for a more intensive preventive strategy to optimize the management of NP lupus.

Human herpesvirus 6 infects the central nervous system of multiple sclerosis patients in the early stages of the disease

The presence and the replicative state of human herpesvirus 6 (HHV-6) were evaluated in clinical samples from multiple sclerosis (MS) patients at the first time of MS diagnosis. HHV-6 variant B was present in peripheral blood mononuclear cells of 5/32 (15%) patients, but persisted with a latent infection. Viral sequences were present also in cerebrospinal fluid (CSF), both free in the liquid (7/32, 22%) and latent in the cellular fraction (3/32, 9%), as shown by analysis of viral transcription. In these cases, variant A was detected. HHV-6 DNA sequences present in the CSF were associated to mature viral particles. In fact, in vitro infectious assays of CSF showed the presence of replication-competent virions. These results show that about 20% of MS patients have active foci of HHV-6 variant A infection in the early stages of the disease and suggest that viral replication takes place within the central nervous system.

Systemic lupus erythematosus presenting with neurological disorders

SummarySix patients are described who developed a wide variety of neurological manifestations heralding systemic lupus erythematosus (SLE), which included epileptic seizures, stroke, peripheral polyradiculoneuro pathy similar to Guillain-Barré syndrome, transverse my elopathy and multifocal disorders with remitting course mimicking multiple sclerosis. The peculiarity of these cases was that the neurological disorders remained the only manifestations of SLE for many years and the nervous system appeared to be the main target even after the development of systemic SLE. In five patients the prognosis was favourable and corticosteroid treatment led to prolonged remission.

Multiple sclerosis in the province of Ferrara : Evidence for an increasing trend

BackgroundEpidemiological studies on the distribution of multiple sclerosis (MS) conducted in the Mediterranean area in the last two decades have disclosed a significant increase in frequency of the disease, indicating caution when a latitude-related model of MS is accepted. Previous descriptive surveys in the province of Ferrara, northern Italy, carried out by our own epidemiological research group, have established that this area is at high risk for MS.ObjectiveTo confirm the above assumption and to update MS frequency estimates in this area.Design and settingWe conducted a community-based intensive prevalence and incidence study, by adopting a complete enumeration approach.ResultsOn December 31, 2004, 423 patients (300 women and 123 men) suffering from definite or probable MS (Posers criteria) living in the province of Ferrara, yielded a crude prevalence rate of 120.93 (95 % CI, 110.05–134.23) per 100,000, 164.26 for women and 73.59 for men. The average incidence from 1990 to 2003 was 4.35 per 100,000 (95 % CI, 3.77–4.99), 5.91 for women and 2.63 for men. The incidence rate,which was relatively stable during the previous 25 years (1965–1989) with a mean rate of 2.3 per 100,000, increased to a value of 3.39 per 100,000 in the period 1990–1994, 4.09 per 100,000 in the period 1995–1999 and 3.84 per 100,000 in the period 2000–2003.ConclusionsThese results confirm that in Ferrara MS occurs more frequently than suggested by the geographic- related distribution model and, based on other recent national surveys, support the view that northern Italy is a high-risk area for the disease. The marked increase in MS prevalence rate, in comparison with previous investigations, is in part due to the increasing survival of patients as a result of improved supportive care and the accumulation of new incidence cases owing to the reduction in diagnostic latency for better quality of neurological diagnostic procedures. The incidence in the province of Ferrara was found to slowly change with an incremental trend,which cannot only be attributed to improvements in diagnostic ability. Environmental risk factors in genetically predisposed people over time could be considered.

T-cell phenotypic profiles in the cerebrospinal fluid and peripheral blood of multiple sclerosis patients

Thirty-nine patients with clinically definite multiple sclerosis (MS) entered the study. Of 28 subjects with a relapsing-remitting course, 19 were classified in acute relapse, 9 in remission; 11 patients had a progressive course without remissions. Furthermore, 6 subjects with inflammatory neurological disease (IND), and 10 with non-inflammatory and non-neoplastic neurological disease (NIND) were investigated. We simultaneously studied cerebrospinal fluid (CSF) and peripheral blood (PB) T-, B- and NK-cell subsets, as defined by following monoclonal antibodies: anti-CD3, -CD4, -CD8, -CD19, -CD16, -HLA-DR and -IL-2-R. We found a significant increase of CD4+ T-cells compared with controls in CSF, with respect to PB, of MS patients, particularly in acute relapse. An increase of HLA-DR+ cell percentages in the CSF than in the PB in all MS groups, especially in attacks of MS but also in remission, was also observed, with a positive correlation between CD4+ T-cell and DR+ cell percentages both in the CSF as well as in the PB of relapsing MS patients. These findings, together with the increase of IL-2-R+ cells in the PB, particularly in relapsing MS, give further support for the presence of a systemic T-cell activation in MS.